Virus-based approaches are known to treat various neurological diseases, through the introduction of therapeutic genes to transduce neuronal and/or support cells. For example, a multicistronic lentiviral vector product, ProSavin®, has been developed to treat Parkinson's disease. ProSavin® mediates intrastriatal dopamine production by transduction into non-dopamine cells the genes for aromatic L-amino acid decarboxylase, tyrosine hydroxylase, and GTP cyclohydrolase I (Azzouz et at (2002) J Neurosci. 22: 10302-10312).
Previous methods of lentiviral vector delivery have introduced the vectors to specific regions within the brain through multiple small volume deposits at a low discontinuous flow rate to ensure sufficient transduction of target cells over a wide area (Azzouz et at (2002) J Neurosci 22: 10302-10312). For example, ProSavin® is administered using multiple tracts (up to 5 per hemisphere) using a step-wise delivery method which involves multiple deposits of the vector along each tract (Jarraya et at (2009) Sci Transl Med 14: 1(2) 2-4).
Such an approach requires complex pre-surgical planning to determine the positioning of the cannula tracts and time-consuming surgery, with an increased risk of bleeding and other surgical complications associated with the use of multiple cannula tracts to introduce the vector.
There is thus a need for improved delivery methods for such lentiviral vectors.
There are reports of using convection-enhanced delivery (CED) as an efficient method of delivering therapeutic agents, including maghemite nanoparticles, liposomes and small viral vectors, such as adeno-associciated virus vectors (AAV), into the brain (Lieberman et at (1985) J. Neurosurg. 82:1021-1029; Bankiewicz et al (2000) Exp. Neurol. 164:2-14; Cunningham et al (2000) Cell Transplant 9:585-594; Nguyen et al (2001) Neuroreport 12:1961-1964; Mamot et al (2004) J Neurooncol. 68:1-9; Hadaczek et al (2006) Hum. Gene Ther 17:291-302 and Perlstein et al (2008) Neuro-Oncol 10:153-161). Using a pressurised infusate, the distribution of particles and macromolecules through the perivascular space has been reported to be enhanced above that achieved by diffusion alone (Chen et al (2004) J. Neurosurg. 101:314-322 and Hadaczek et al (2009) Hum. Gene Ther 20:229-237).
CED uses a pressure gradient established at the tip of an infusion catheter that initially creates bulk flow that “pushes” the therapeutic agent through the space between brain cells.
Although there are reports of successful use of CED to deliver small AAVs (Bankiewicz et al (2000) Exp. Neurol. 164:2-14; Cunningham et al (2000) Cell Transplant 9:585-594; and Hadaczek et al (2009) Hum. Gene Ther 20:229-237) these findings have little impact on the delivery of lentiviral vectors, because the intracellular space in the brain has been calculated as being between 38 and 64 nm (Thorne and Nicholson (2006) PNAS 104; 5567-5572), whereas the typical diameter of lentiviruses is around 100 nm, typically around four-fold larger than AAV vectors (Fields Virology Fifth Edition (2007) Eds. Knipe and Howley. Lippincott Williams and Wilkins). AAV vectors are non-enveloped viruses with a diameter of around 18-26 nm and are considerably smaller than the calculated intracellular space.
Consideration to the cellular tropism (Davidson et al (2000) Proc. Natl. Acad. Sci. USA, Vol. 97, PP. 3428-3432; Azzouz et al (2002) J Neurosci 22:10302-10312 and Eschemacher et al (2004) Exp Med 90:61-69) is an important factor when changing vector delivery, as neuronal or other cellular targets may be significantly compromised when vectors are delivered in an accelerated fashion. Moreover, the relative immunological response to central vector administration may also be altered when modifying the methodology for surgical administration into specific brain regions.